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Ofatumumab Granted Priority Review as Maintenance Therapy in Chronic Lymphocytic Leukemia
The U.S. FDA granted priority review to
the supplemental biologics license application (sBLA) filed for ofatumumab
as maintenance therapy in patients with
relapsed CLL, following a response to
second- or third-line therapy. Ac-
ceptance of the sBLA was based on
the results of the phase III, open-label
PROLONG study that randomized 474
patients to receive ofatumumab (n=238)
or to undergo observation only (control;
n=236). During the first cycle, ofatu-
mumab was administered at 300 mg
followed one week later by a 1,000-mg
dose. During subsequent cycles, the
drug was administered at 1,000 mg every eight weeks for up to two years. The
study’s primary endpoint was PFS, and
secondary endpoints included duration
of response, OS, and safety.
Patients in the treatment group had
a median PFS of 30.4 months compared
5.14 Lactose
Since the capsules contain lactose, Tasigna is not recommended for patients
with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or
of glucose-galactose malabsorption.
5.15 Monitoring Laboratory Tests
Complete blood counts should be performed every 2 weeks f or the first
2 months and then monthly thereafter. Perform chemistry panels, including
electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose
prior to therapy and periodically. ECGs should be obtained at baseline,
7 days after initiation and periodically thereafter, as well as following dose
adjustments [see Warnings and Precautions (5.2)]. Monitor lipid profiles
and glucose periodically during the first year of Tasigna therapy and at least
yearly during chronic therapy. Should treatment with any HMG-CoA reductase inhibitor (a lipid lowering agent) be needed to treat lipid elevations,
evaluate the potential for a drug-drug interaction before initiating therapy as
certain HMG-CoA reductase inhibitors are metabolized by the CYP3A4 pathway [see Drug Interactions (7.1) in the full prescribing information].
Assess glucose levels before initiating treatment with Tasigna and monitor
during treatment as clinically indicated. If test results warrant therapy,
physician should follow their local standards of practice and treatment
guidelines.
5.16 Embryo-Fetal Toxicity
There are no adequate and well controlled studies of Tasigna in pregnant
women. However, Tasigna may cause fetal harm when administered to a
pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at
maternal exposures that were lower than the expected human exposure at
the recommended doses of nilotinib. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus. Women of child-bearing
potential should avoid becoming pregnant while taking Tasigna [see Use in
Specific Populations (8.1) in the full prescribing information].
5.17 Fluid Retention
In the randomized trial in patients with newly diagnosed Ph+ CML in
chronic phase, severe (Grade 3 or 4) fluid retention occurred in 3.9% and
2.9% of patients receiving Tasigna 300 mg bid and 400 mg bid, respectively, and in 2.5% of patients receiving imatinib. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema, were
observed in 2.2% and 1.1% of patients receiving Tasigna 300 mg bid and
400 mg bid, respectively, and in 2.1% of patients receiving imatinib. Effusions were severe (Grade 3 or 4) in 0.7% and 0.4% of patients receiving
Tasigna 300 mg bid and 400 mg bid, respectively, and in no patients receiving imatinib. Similar events were also observed in postmarketing reports.
Monitor patients for signs of severe fluid retention (e.g., unexpected rapid
weight gain or swelling) and for symptoms of respiratory or cardiac compromise (e.g., shortness of breath) during Tasigna treatment; evaluate etiology and treat patients accordingly.
6 ADVERSE REACTIONS
The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed
Warning, Warnings and Precautions (5)].
• Myelosuppression [see Warnings and Precautions (5.1)]
• QT Prolongation [see Boxed Warning, Warnings and Precautions (5.2)]
• Sudden Deaths [see Boxed Warning, Warnings and Precautions (5.3)]
• Cardiac and Arterial Vascular Occlusive Events [see Warnings and Precautions (5.4)]
• Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions
(5.5)]
• Hepatotoxicity [see Warnings and Precautions (5.6)]
• Electrolyte Abnormalities [see Boxed Warning, Warnings and Precautions
(5.7)]
• Hemorrhage [see Warnings and Precautions (5.12)]
• Fluid Retention [see Warnings and Precautions (5.17)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
In Patients with Newly Diagnosed Ph+ CML-CP
The data below reflect exposure to Tasigna from a randomized trial in
patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice-daily (n=279). The median time on treatment in the nilotinib 300 mg twice-daily group was 61 months (range 0.1
to 71 months). The median actual dose intensity was 593 mg/day in the
nilotinib 300 mg twice-daily group.
The most common (>10%) non-hematologic adverse drug reactions were
rash, pruritus, headache, nausea, fatigue, alopecia, myalgia and upper
abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, arthralgia,
abdominal pain, peripheral edema, vomiting, and asthenia were observed
with 14.8 months in the control group
(p<0.0001). After a median follow-up of
19.1 months, the median OS had not yet
been determined in the two treatment
groups. The median treatment duration in the ofatumumab group was 12.5
months. The most commonly reported
grade ≥3 adverse events associated with
ofatumumab included neutropenia and
infections.
less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction.
Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%)
in the 300 mg twice-daily treatment group. No patient had an absolute QTcF
of >500 msec while on study drug.
The most common hematologic adverse drug reactions (all grades) were
myelosuppression including: thrombocytopenia (18%), neutropenia (15%)
and anemia (8%). See Table 7 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse reactions, regardless of relationship to study
drug, was observed in 10% of patients.
In Patients with Resistant or Intolerant Ph + CML-CP and CML-AP
In the single open-label multicenter clinical trial, a total of 458 patients with
Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior
therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the
recommended dose of 400 mg twice-daily.
The median duration of exposure in days for CML-CP and CML-AP patients
is 561 (range 1 to 1096) and 264 (range 2 to 1160), respectively. The
median dose intensity for patients with CML-CP and CML-AP is 789 mg/day
(range 151 to 1110) an d 780 mg/day (range 150 to 1149), respectively and
corresponded to the planned 400 mg twice-daily dosing.
The median cumulative duration in days of dose interruptions for the CML-CP
patients was 20 (range 1 to 345), and the median duration in days of dose
interruptions for the CML-AP patients was 23 (range 1 to 234).
In patients with CML-CP, the most commonly reported non-hematologic
adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue,
headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia.
In patients with CML-AP, the most commonly reported non-hematologic
adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial
hemorrhage, elevated lipase and pyrexia.
Sudden deaths and QT prolongation were reported. The maximum mean
QTcF change from baseline at steady-state was 10 msec. Increase in QTcF
>60 msec from baseline was observed in 4.1% of the patients and QTcF of
>500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.6) in the full
prescribing information].
Discontinuation due to adverse drug reactions was observed in 16% of
CML-CP and 10% of CML-AP patients.
Most Frequently Reported Adverse Reactions
Tables 5 and 6 show the percentage of patients experiencing non-hematologic
adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of
patients who received at least 1 dose of Tasigna are listed.
Table 5: Most Frequently Reported Non-hematologic Adverse Reactions
(Regardless of Relationship to Study Drug) in Patients with Newly
Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg Twice-Daily or
Imatinib 400 mg Once-Daily Groups) 60-Month Analysisa
Patients with Newly Diagnosed
Ph+ CML-CP
TASIGNA Imatinib TASIGNA Imatinib
300 mg 400 mg 300 mg 400 mg
twiceoncetwiceoncedaily
daily
daily
daily
N=279
Body System and Preferred Term
N=280
All Grades (%)
N=279
N=280
CTC Gradesb
3/4 (%)
Skin and
subcutaneous
tissue disorders
Rash
Pruritus
Alopecia
Dry skin
38
21
13
12
19
7
7
6
<1
<1
0
0
2
0
0
0
Gastrointestinal
disorders
Nausea
Constipation
Diarrhea
Vomiting
Abdominal pain
upper
Abdominal pain
Dyspepsia
22
20
19
15
41
8
46
27
2
<1
1
<1
2
0
4
<1
18
15
10
14
12
12
1
2
0
<1
0
0
Headache
Dizziness
32
12
23
11
3
<1
<1
<1
Nervous system
disorders
(continued)